ANKRD44

Chr 2

ankyrin repeat domain 44

Also known as: ARSB, PP6-ARS-B

NCBI Gene: 91526 ENSG00000065413 UniProt: Q8N8A2 OMIM: 620861

The protein functions as a putative regulatory subunit of protein phosphatase 6 (PP6) involved in recognizing phosphoprotein substrates. Mutations cause autosomal recessive intellectual disability with seizures and spasticity. This gene is moderately constrained against loss-of-function variants, with developmental delays and neurological symptoms typically manifesting in early childhood.

OMIM ResearchSummary from UniProt

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.53

Clinical Summary— ANKRD44

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 121 VUS of 144 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.53LOEUF

pLI 0.337

Z-score 2.97

OE 0.23 (0.11–0.53)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.03Z-score

OE missense 0.80 (0.71–0.91)

171 obs / 213.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.23 (0.11–0.53)

0≤0.351.4

Missense OE?0.80 (0.71–0.91)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 4 / 17.4Missense obs/exp: 171 / 213.3Syn Z: 0.80

This gene — mechanism propensity

0.6162th %ile

GOF

0.6735th %ile

LOF

0.3842th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

144 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS121

Likely Benign1

Likely Pathogenic

121

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Total
Pathogenic	0	0	0
Likely Pathogenic	0	1	1
VUS	121	0	121
Likely Benign	1	0	1
Benign	0	0	0
Total	122	1	123

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

35 pathogenic / likely-pathogenic (of 41) ClinVar copy-number / structural variants overlap ANKRD44 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →